UBE2M Drives Hepatocellular Cancer Progression as a p53 Negative Regulator by Binding to MDM2 and Ribosomal Protein...

Area of Science:

• Molecular Oncology
• Cancer Biology
• Biochemistry

Background:

• UBE2M (Ubiquitin-conjugating enzyme E2 M), an E2 NEDD8-conjugating enzyme, is overexpressed in hepatocellular carcinoma (HCC) cell lines (HepG2, Hep3B, Huh7, PLC/PRF5) and associated with poor prognosis.
• The precise oncogenic mechanism of UBE2M in HCC remains largely undetermined.

Purpose of the Study:

• To elucidate the underlying oncogenic mechanism of UBE2M in hepatocellular carcinoma (HCC).
• To investigate the role of UBE2M in regulating the tumor suppressor protein p53 within HCC cells.

Main Methods:

• Utilized UBE2M depletion in HCC cell lines (HepG2, Huh7, Hep3B) to assess effects on cell viability, proliferation, cell cycle, and apoptosis.
• Investigated the interaction between UBE2M, MDM2, ribosomal protein L11, and p53 using co-immunoprecipitation and immunofluorescence.
• Assessed tumor growth in vivo using athymic nude mice xenograft models with UBE2M-depleted HepG2 cells.

Main Results:

• UBE2M depletion significantly suppressed HCC cell viability and proliferation, inducing cell cycle arrest and apoptosis via PARP and caspase 3 cleavage, and upregulating p53, Bax, and PUMA.
• UBE2M depletion enhanced p53 expression and stability, while UBE2M overexpression promoted p53 degradation mediated by MDM2.
• UBE2M directly binds to MDM2 and ribosomal protein L11, facilitating p53 degradation and promoting HCC progression; L11 is crucial for p53 activation upon UBE2M depletion. In vivo studies confirmed tumor growth retardation with UBE2M depletion.

Conclusions:

• UBE2M functions as a negative regulator of p53 in HCC, promoting cancer progression.
• UBE2M promotes HCC tumorigenesis by interacting with MDM2 and ribosomal protein L11, leading to p53 destabilization and inactivation.
• Targeting UBE2M represents a potential therapeutic strategy for hepatocellular carcinoma.